合成路线:The protected hydroxyproline tosylate (I) was condensed with the sodium derivative of thiophenol (II) to produce thioether (III).After saponification of the methyl ester function of (III),the N-benzyloxycarbonyl group of (IV) was removed by means of HBr in refluxing HOAc,yielding cis-4-(phenylthio)-L-proline (V).Acylation of (V) with (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) afforded zofenopril (VII),which was finally converted to the corresponding calcium salt by treatment with calcium oxide in EtOH/H2O.The intermediate (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) was obtained by enzymatic resolution of racemic 3-(benzoylthio)-2-methylpropionic acid (VIII) with Pseudomonas fluorescens (Amano lipase P-30) to yield (S)-3-(benzoylthio)-2-methylpropionic acid (IX),which was activated with oxalyl chloride to afford the chiral acyl chloride (VI).
参考文献标题:A process for the preparation of zofenopril calcium salt
文献作者:Giachetti,A.; Giorgi,R.; Mannucci,C.; Falezza,A.(Menarini Industrie Farma Riunite Srl)
参考来源:EP 1102745; JP 2002522417; WO 0007984
合成路线:The protected hydroxyproline tosylate (I) was condensed with the sodium derivative of thiophenol (II) to produce thioether (III).After saponification of the methyl ester function of (III),the N-benzyloxycarbonyl group of (IV) was removed by means of HBr in refluxing HOAc,yielding cis-4-(phenylthio)-L-proline (V).Acylation of (V) with (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) afforded zofenopril (VII),which was finally converted to the corresponding calcium salt by treatment with calcium oxide in EtOH/H2O.The intermediate (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) was obtained by enzymatic resolution of racemic 3-(benzoylthio)-2-methylpropionic acid (VIII) with Pseudomonas fluorescens (Amano lipase P-30) to yield (S)-3-(benzoylthio)-2-methylpropionic acid (IX),which was activated with oxalyl chloride to afford the chiral acyl chloride (VI).
参考文献标题:Enzymatic resolution process hydrolyzing thio-ester
文献作者:Patel,R.N.; Howell,J.M.; Szarka,L.J.(Bristol-Myers Squibb Co.)
参考来源:US 5128263
合成路线:The protected hydroxyproline tosylate (I) was condensed with the sodium derivative of thiophenol (II) to produce thioether (III).After saponification of the methyl ester function of (III),the N-benzyloxycarbonyl group of (IV) was removed by means of HBr in refluxing HOAc,yielding cis-4-(phenylthio)-L-proline (V).Acylation of (V) with (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) afforded zofenopril (VII),which was finally converted to the corresponding calcium salt by treatment with calcium oxide in EtOH/H2O.The intermediate (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) was obtained by enzymatic resolution of racemic 3-(benzoylthio)-2-methylpropionic acid (VIII) with Pseudomonas fluorescens (Amano lipase P-30) to yield (S)-3-(benzoylthio)-2-methylpropionic acid (IX),which was activated with oxalyl chloride to afford the chiral acyl chloride (VI).
合成路线:The Grignard condensation of N-(benzyloxycarbonyl)-4-oxo-L-proline (XXIX) with phenylmagnesium bromide gives the 4-hydroxy-4-phenylproline derivative (XXX),which is dehydrated with TFA yielding the dehydroproline (XXXI).The hydrogenation of (XXXI) with Li in liquid ammonia affords the previously reported trans-4-phenyl-L-proline (XIX),which is hydrogenated to the corresponding cyclohexyl derivative (XI) with H2 over PtO2.
合成路线:A new synthesis of spirapril has been reported:The cyclization of N-benzyloxycarbonyl-4-oxo-(S)-proline (I) with ethandithiol by means of boron trifluoride ethearate in dichloromethane gives 7-(benzyloxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (II),which is treated with concentrated HCl to yield 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (III).The protection of (III) with tert-butoxycarbonyl chloride and with trimethylsilylethanol in the usual manner affords N-(tert-butoxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxyli c acid 2-(trimethylsilyl)ethyl ester (IV),which is condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (V) by a first treatment with p-toluenesulfonic acid and a condensation step with dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HBT),giving spirapril 2-(trimethylsilyl)ethyl ester (VI).Finally,this ester is hydrolyzed with tetrabutylammonium fluoride trihydrate in DMF.
参考文献标题:Angiotensin-converting enzyme inhibitors.Mercaptan,carboxyalkyl dipeptide,and phosphinic acid inhibitors incorporating 4-substituted prolines
文献作者:Krapcho,J.; Turk,C.; Cushman,D.W.; Powell,J.R.; DeForrest,J.M.; Spitzmiller,E.R.; Karanewsky,D.S.; Duggan,M.; Rovnyak,G.; Schwartz,J.; et al.
参考来源:J Med Chem 1988,31(6),1148
产品链接: CAS No. 81938-43-4›› 产品链接: CAS No.81872-10-8››